CN102971348B - Adjustable LCST polymkeric substance and preparation method thereof - Google Patents

Adjustable LCST polymkeric substance and preparation method thereof Download PDF

Info

Publication number
CN102971348B
CN102971348B CN201180033546.1A CN201180033546A CN102971348B CN 102971348 B CN102971348 B CN 102971348B CN 201180033546 A CN201180033546 A CN 201180033546A CN 102971348 B CN102971348 B CN 102971348B
Authority
CN
China
Prior art keywords
group
alkyl
monomer composition
hydrogen atom
polymkeric substance
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CN201180033546.1A
Other languages
Chinese (zh)
Other versions
CN102971348A (en
Inventor
D·普特南
L·黄
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cornell University
Original Assignee
Cornell University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cornell University filed Critical Cornell University
Priority to CN201510556416.6A priority Critical patent/CN105175623A/en
Publication of CN102971348A publication Critical patent/CN102971348A/en
Application granted granted Critical
Publication of CN102971348B publication Critical patent/CN102971348B/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
    • C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
    • C08F220/10—Esters
    • C08F220/26—Esters containing oxygen in addition to the carboxy oxygen
    • C08F220/28—Esters containing oxygen in addition to the carboxy oxygen containing no aromatic rings in the alcohol moiety
    • C08F220/285—Esters containing oxygen in addition to the carboxy oxygen containing no aromatic rings in the alcohol moiety and containing a polyether chain in the alcohol moiety
    • C08F220/286—Esters containing oxygen in addition to the carboxy oxygen containing no aromatic rings in the alcohol moiety and containing a polyether chain in the alcohol moiety and containing polyethylene oxide in the alcohol moiety, e.g. methoxy polyethylene glycol (meth)acrylate
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
    • C08F220/00—Copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and only one being terminated by only one carboxyl radical or a salt, anhydride ester, amide, imide or nitrile thereof
    • C08F220/02—Monocarboxylic acids having less than ten carbon atoms; Derivatives thereof
    • C08F220/52—Amides or imides
    • C08F220/54—Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide
    • C08F220/58—Amides, e.g. N,N-dimethylacrylamide or N-isopropylacrylamide containing oxygen in addition to the carbonamido oxygen, e.g. N-methylolacrylamide, N-(meth)acryloylmorpholine
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G61/00—Macromolecular compounds obtained by reactions forming a carbon-to-carbon link in the main chain of the macromolecule
    • C08G61/02—Macromolecular compounds containing only carbon atoms in the main chain of the macromolecule, e.g. polyxylylenes
    • C08G61/04—Macromolecular compounds containing only carbon atoms in the main chain of the macromolecule, e.g. polyxylylenes only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09D—COATING COMPOSITIONS, e.g. PAINTS, VARNISHES OR LACQUERS; FILLING PASTES; CHEMICAL PAINT OR INK REMOVERS; INKS; CORRECTING FLUIDS; WOODSTAINS; PASTES OR SOLIDS FOR COLOURING OR PRINTING; USE OF MATERIALS THEREFOR
    • C09D133/00—Coating compositions based on homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by only one carboxyl radical, or of salts, anhydrides, esters, amides, imides, or nitriles thereof; Coating compositions based on derivatives of such polymers
    • C09D133/04—Homopolymers or copolymers of esters
    • C09D133/06—Homopolymers or copolymers of esters of esters containing only carbon, hydrogen and oxygen, the oxygen atom being present only as part of the carboxyl radical
    • C09D133/062—Copolymers with monomers not covered by C09D133/06
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
    • G01N21/17—Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/25—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
    • G01N21/27—Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands using photo-electric detection ; circuits for computing concentration

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Polymers & Plastics (AREA)
  • Physics & Mathematics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Materials Engineering (AREA)
  • Wood Science & Technology (AREA)
  • Spectroscopy & Molecular Physics (AREA)
  • Theoretical Computer Science (AREA)
  • Mathematical Physics (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Immunology (AREA)
  • Pathology (AREA)
  • Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

This application describes the polymer composition with following chemical structure: and for the production of the monomer composition of described polymkeric substance.Application also describes the method for the combinatorial library of these polymkeric substance of preparation and these polymkeric substance.

Description

Adjustable LCST polymkeric substance and preparation method thereof
The cross reference of related application
This application claims the right of priority of the U.S. Provisional Application numbers 61/331,987 submitted on May 6th, 2010.
Government-funded
The present invention by National Science Foundation and rub that root tissue project fund can provide funds be numbered the government-funded of the fund of CBET-0642509 under complete.Government enjoys certain right to the present invention.
Invention field
The present invention relates generally to the composition of lower critical solution temperature (LCST) polymkeric substance, and preparation method and use.
Background technology
In aqueous solution, LCST polymkeric substance reveals unexpected Volume-phase transition at critical (i.e. LCST) thermometer.When temperature is increased to higher than LCST, assuming that the hydrophobicity of polymer chain increases suddenly, it causes polymkeric substance almost insoluble in aqueous solution.This peculiar property of LCST polymkeric substance make its such as control or revise bacterial accumulation, absorbing proteins and release, protein ligand identification and drug delivery reagent this type of application in be subject to special concern.
But, to be integrated in these application and following application faced by a significant obstacle be that it almost can not by any one derivatize in the functional group of plurality of optional.When not possessing this ability, will be very limited to the use of this base polymer and operable condition thereof.Such as, the character of existing LCST polymkeric substance is very difficult to fine adjustment usually, because generally can not carry out accurate adjustment to its structure.Some lacks the specific LCST polymkeric substance of this ability for poly-(N-replacement) acrylamide.Therefore, by its structure is carried out suitable accurate adjustment just can regulate such as critical temperature and and host between the interact LCST polymkeric substance of character of ability there is significant advantage.
Invention summary
First aspect of the present invention relates to the monomer composition used in the LCST polymkeric substance described in preparation the application.In a specific embodiment, the chemical structure of monomer composition is as follows:
In formula (I), R 1and R 2independently selected from hydrogen atom or the alkyl containing at least one carbon atom; X represents-O-or-NR 5-group; And Y represents-O-,-S-or-NR 3r 4-group.Substituent R 3, R 4, and R 5represent hydrogen atom or the alkyl containing at least one carbon atom independently, in addition, R 3and R 4in one can represent lone-pair electron.Subscript n represent be at least 1,2,3 or 4 integer, subscript m represent 0 or be at least 1,2 or 3 integer.
In second, the present invention relates to the polymer composition that any monomer composition is by mentioned earlier derived by polyreaction.In a specific embodiment, the chemical structure of polymer composition is as follows:
In formula (13), R 1, R 2, X, Y, R 3, R 4, R 5, m with n be with identical to the definition of monomer composition above.Subscript p represent be at least 2 integer.
In the 3rd, the present invention relates to the method for producing polymkeric substance according to above-mentioned polymerization general formula.Described method comprises is polymerized monomer composition mentioned above by any suitable method.In a specific embodiment, described polymerization process is RAFT or ATRP polymerization method.
In the 4th, the present invention relates to the combinatorial library of LCST polymkeric substance, in storehouse, the one or more of polymkeric substance are selected from X, Y, R 1, R 2, n, m and p variable change.Relevant to this embodiment is that a kind of high flux screening LCST combination of polymers library is effectively to illustrate the method for its LCST and other character.
Accompanying drawing is sketched
Figure 1A, B show (A) monomer CTMAAm(iii) synthesis and there is polymerization by RAFT, and (B) brush-type polymkeric substance pCTMAAm(vi) schematic diagram of structure.
Fig. 2 A, B shows (A) at [M] 0/ [CTA] 0/ [I] 0under=200:1:0.25 condition, M nexperiment (GPC), M ntheoretical and PDI(GPC) with the relation of CTMAAm RAFT polymerization conversion, and (B) different [M] 0/ [CTA] 0/ [I] 0the pseudo-first order kinetics curve of ratio.Dotted line represents when chain growth is in time linear, based on the linear regression curves that the short period calculates.
The schematic diagram of the preparation in polymkeric substance library is shown in Fig. 3: figure, wherein by using pCTMAAm(with hydrophilic carboxylic acid's capping group) also use hydrophobicity N substituted amide group (-NHR as masterplate, wherein R is alkyl group) replace the part of carboxylic acid-terminated group, thus the systematicness of implementation structure parameter changes.
Show in Fig. 4: figure in the polymkeric substance library changed at propyl group, butyl and hexyl capping group, concentration is the transmissivity of polymers soln when 500nm and the dependency of temperature of 3mg/mL.
The LCST polymkeric substance of propyl group, butyl and hexyl capping group change and the dependency of Replacement rate is shown in Fig. 5 A-C: figure.
The LCST polymkeric substance of propyl group, butyl and hexyl capping group change and the dependency of pH is shown in Fig. 6 A-C: figure.
Fig. 7: three phase diagram shows the dependency between three kinds of parameters of LCST in LCST polymkeric substance library, comprises Replacement rate, the molecular weight of polymkeric substance and the carbonatoms of linking group.
Detailed Description Of The Invention
For simplicity, before the present invention is described further, first provide some term used in specification sheets, embodiment and claims herein.These definition should be understood according to the understanding of content disclosed in the present application and those skilled in the art.
The term " alkyl " used in the application or " hydrocarbon connexon " are, in first embodiment, only comprise carbon and hydrogen.In different embodiments, one or more described alkyl or connexon can comprise accurately, or it is minimum, or at most, such as, one, two, three, four, five, six, seven, eight, nine, ten, 11,12,13,14,15,16,17,18, nineteen or 20 carbon atoms, or with several carbon atoms of any two specified ranges that are border in above-mentioned carbonatoms.Alkyl in the different positions of the different compound described by the application or compound or connexon, can have identical or different carbonatoms (or its preferred scope), to adjust or to optimize activity or other character of compound independently.
Described alkyl or connexon can be, such as, and saturated and straight chain (that is, straight chained alkyl or thiazolinyl connexon).Some example of straight chained alkyl (or thiazolinyl connexon) comprises methyl (or methylene radical connexon, that is ,-CH 2-or methyne connexon), ethyl (or vinyl or dimethylene connexon, that is ,-CH 2cH 2-connexon), n-propyl, normal-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecane base, dodecyl, n-tridecane base, n-tetradecane base, Pentadecane base, n-hexadecyl, n-heptadecane base, Octadecane base and NSC 62789 base (or its connexon analogue) separately.
Described alkyl or connexon can be saturated with side chain (that is, branched-chain alkyl or thiazolinyl connexon) alternatively.Some example of branched-chain alkyl comprises sec.-propyl, isobutyl-, sec-butyl, the tertiary butyl, isopentyl, neo-pentyl, 2-methyl amyl, 3-methyl amyl and a lot of C 7, C 8, C 9, C 10, C 11, C 12, C 13, C 14, C 15, C 16, C 17, C 18, C 19, and C 20alkyl that is saturated and side chain.Some example of branched-chain alkenyl connexon is those connexons (such as, isopropyl alkene, the-CH (CH derived after one of aforementioned exemplary branched-chain alkyl removing hydrogen atom 3) CH 2-).
Described alkyl or connexon can be saturated with ring-type (that is, cycloalkyl or cycloalkenyl group connexon) alternatively.Some example of cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl and ring octyl group.Cycloalkyl also can be the group of many rings (such as, dicyclo), can have a key (such as, dicyclohexyl) or share (that is, condensing) limit (such as, perhydronaphthalene and norcamphane) between two rings.Some example of cycloalkenyl group connexon is those connexons derived after one of aforementioned exemplary cycloalkyl removing hydrogen atom.
Described alkyl or connexon can be undersaturated and straight chain (that is, straight chain alkene race or thiazolinyl or connexon) alternatively.Unsaturated by there is one or more carbon-to-carbon double bond and/or the embodiment of one or more carbon-to-carbon triple bond.Some example of straight chain alkene race comprises vinyl, propylene-1-base (propylene), 3-butylene-l-base (CH 2=CH-CH 2-CH 2-), 2-butylene-l-base (CH 2-CH=CH-CH 2-), butadienyl, 4-amylene-l-base, 3-amylene-l-base, 2-amylene-l-base, 2,4-pentadiene-1-base, 5-hexene-l-base, 4-hexene-l-base, 3-hexene-l-base, 3,5-hexadiene-l-base, 1,3,5-hexatriene-l-base, 6-heptene-l-base, ethynyl, proyl (2-propynyl) and a lot of C 7, C 8, C 9, C 10, C 11, C 12, and more senior unsaturation and straight-chain alkyl.Some example of straight chain alkene race connexon is those connexons (such as, vinylene ,-CH=CH-or vinylidene) derived after one of aforementioned exemplary straight-chain alkenyl removing hydrogen atom.
Described alkyl or connexon can be undersaturated and side chain (that is, propping up alkene race or thiazolinyl or connexon) alternatively.Some example of branched-chain alkenyl comprises propylene-2-base (CH 2=C.-CH 3), 3-butene-2 base (CH 2=CH-CH.-CH 3), 3-butylene-3-base (CH 2=C.-CH 2-CH 3), 4-2-pentenyl, 4-amylene-3-base, 3-2-pentenyl, 3-amylene-3-base, 2,4-pentadiene-3-bases and a lot of C 6, C 7, C 8, C 9, C 10, C 11, C 12, and more senior unsaturation and branched hydrocarbyl.Some example propping up alkene race connexon is those connexons derived after one of aforementioned exemplary branched-chain alkenyl removing hydrogen atom.
Described alkyl or connexon can be undersaturated and ring-type (that is, cycloalkenyl group or ring alkenylene connexon) alternatively.Unsaturated and cyclic group can be fragrance or fat.Unsaturated and some example that is cyclic group comprises cyclopropenyl radical, cyclobutene base, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, phenyl, benzyl, cycloheptenyl, cycloheptadiene base, cyclooctene base, cyclooctadiene base and cyclooctatetraenyl.Unsaturated cyclic hydrocarbon radical also can be the group of many rings (such as, dicyclo or the many aromatic groups of three rings), can have a key (such as, biphenyl) or share (that is, condensing) limit, as naphthalene, anthracene, Fei, Fu or indenes between two rings.Some example of ring alkenylene connexon is those connexons (such as, phenylene and biphenylene) derived after one of aforementioned exemplary cycloalkenyl group removing hydrogen atom.
(namely one or more described alkyl or connexon can also comprise one or more heteroatoms, non-carbon and non-hydrogen atom), as being selected from one or more heteroatomss of oxygen, nitrogen, sulphur and halogen atom, and containing one or more these heteroatomic groups (that is, containing heteroatomic group).Some example of oxy radical comprises hydroxyl (OH), containing carbonyl (such as, carboxylic acid, ketone, aldehyde, carboxylicesters, acid amides and urea functional group), nitro (NO 2), carbon-oxygen-carbon (ether), alkylsulfonyl and sulfinyl (that is, sulfoxide) and amine oxide group.Ether can also be polyalkylene oxide base, as polyethylene oxide group.Some example of nitrogen-containing group comprises primary amine, secondary amine, tertiary amine, quaternary amine, prussiate (that is, nitrile), acid amides (that is ,-C (O) NR 2or-NRC (O), wherein R is independently selected from hydrogen atom and alkyl, as described above), nitro, urea, imino-and carbaminate, is wherein understandable that quaternary amines necessarily with positive charge and balance anion.Some example of sulfur-containing group comprises sulfydryl (that is ,-SH), thioether (that is, sulfide), disulphide, sulfoxide, sulfone, sulfonate and sulfate group.In the application, some example of halogen atom comprises fluorine, chlorine and bromine.Between the carbon atom that one or more heteroatoms as described above (such as, oxygen, nitrogen and/or sulphur atom) can insert any alkyl mentioned above (such as ,-O-,-NR-or-S-), to form alkyl or the connexon of hybrid atom MCM-41.Or, or in addition, in alkyl or connexon, one or morely can replace one or more hydrogen atom containing heteroatomic group.
In a specific embodiment, described alkyl is or comprises cyclic group.Cyclic hydrocarbon radical can be such as monocycle, containing the single ring not being connected with other ring or condensing.Cyclic hydrocarbon radical or can be, such as, dicyclo, three rings, Fourth Ring, or more ring system, it has at least two rings and is interconnected and/or condenses.
In some embodiments, described cyclic hydrocarbon radical is carbocyclic ring, namely not containing ring hetero atom (that is, only containing ring carbon atom).In different embodiments, ring carbon atom in carbon ring group is all saturated, or the part in ring carbon atom is undersaturated, or ring carbon atom is all undersaturated (as aromatic carbon ring group, they can be monocycle, dicyclo, three rings or more senior multiring aromatic group).
In some embodiments, described alkyl is or the ring-type that comprises containing at least one ring hetero atom or polycyclic moiety (such as, one, two, three, four, or more heteroatoms).In this application this type of cyclic group replaced through ring hetero atom is called " heterocyclic group ".As used in this application, " ring hetero atom " refers to the atom (typically, being selected from nitrogen, oxygen and sulphur) being different from carbon and hydrogen of insertion or substituted ring carbon atom in hydrocarbon ring structure.In some embodiments, heterocyclic radical is saturated, and in other embodiments, heterocyclic radical be undersaturated (namely, aliphatic or fragrant heterocyclic radical, wherein said fragrant heterocyclic radical in this application also referred to as " hetero-aromatic ring ", maybe when having two fused rings at least, when wherein at least one contains at least one ring hetero atom, also referred to as " assorted virtue condenses ring system ").In some embodiments, heterocyclic group is connected with another group (that is, not by hydrogen atom and adjacent annular atoms) by its ring carbon atom, and one or more ring hetero atom is not connected with other group.In other embodiments, heterocyclic group is connected with another group by its heteroatoms, and ring carbon atom can with or be not connected with another group.
Some example of saturated heterocyclic group comprises those groups containing at least one Sauerstoffatom (such as, trimethylene oxide, tetrahydrofuran (THF), tetrahydropyrans, 1, 4-dioxane, 1, 3-dioxane, with 1, 3-diepoxy hexane ring), those groups containing at least one nitrogen-atoms (such as, tetramethyleneimine, piperidines, piperazine, tetrahydroglyoxaline, azepines, with decahydroquinoline ring), those groups containing at least one sulphur atom (such as, tetramethylene sulfide, tetrahydric thiapyran, 1, 4-dithiane, 1, 3-dithiane, with 1, 3-bis-thiophene penta ring ring), those groups containing at least one Sauerstoffatom and at least one nitrogen-atoms (such as, morpholine and oxazolidine ring), those groups containing at least one Sauerstoffatom and at least one sulphur atom (such as, 1, 4-thiophene oxane), and those groups containing at least one nitrogen-atoms and at least one sulphur atom (such as, thiazolidine and parathiazan ring).
Some example of unsaturated heterocycle group comprises those groups (such as, the furans containing at least one Sauerstoffatom, pyrans, Isosorbide-5-Nitrae-Dioxins, with dibenzo Dioxins ring), those groups (such as, the pyrroles containing at least one nitrogen-atoms, imidazoles, pyrazoles, pyridine, pyrazine, pyrimidine, 1,3,5-triazines, azepines, two azepines, indoles, purine, benzoglyoxaline, indazole, 2,2'-bis-pyridine, quinoline, isoquinoline 99.9, phenanthroline, Isosorbide-5-Nitrae, 5,6-tetrahydropyrimidine, 1,2,3,6-tetrahydropyridine, 1,2,3,4-tetrahydroquinoline, quinoxaline, quinazoline, pyridazine, cinnolines, 5,6,7,8-tetrahydroquinoxaline, 1,8-naphthyridines, with 4-azabenzimidazoles ring), those groups (such as, the thiophene containing at least one sulphur atom, benzo-thiophene, with thionaphthene ring), containing those groups (such as, the oxazole of at least one Sauerstoffatom with at least one nitrogen-atoms, isoxzzole, benzoxazoles, benzisoxa oxazole, oxazoline, 1,2,5-oxadiazoles (furazan), with 1,3,4-oxadiazoles ring), and containing those groups (such as, the thiazole of at least one nitrogen-atoms with at least one sulphur atom, isothiazole, benzothiazole, benzisothiazole, thiazoline, with 1,3,4-Thiadiazole).
In one aspect, the present invention relates to the vinyl monomer composition with following chemical structure:
In formula (1), R 1and R 2independently selected from hydrogen atom or the alkyl containing at least one carbon atom.Typically, R 1hydrogen atom or methyl.In a specific embodiment, R 2be have at least one, two, three, four or five carbon atoms and there is the straight or branched alkyl of six, seven, eight, nine, ten, 11 or 12 carbon atoms at the most.In other embodiment, R 2be carbon ring group, it can be saturated cyclic group, aliphatics cyclic group or fragrant cyclic group.X represents-O-or-NR 5-group, and Y represents-O-,-S-, Huo – NR 3r 4-group (Qi Zhong – NR 3r 4-in dash represent only atom N place become key), wherein R 3, R 4, and R 5represent hydrogen atom or the alkyl containing at least one carbon atom independently.When for alkyl, R 3, R 4, and R 5typically be the straight or branched alkyl containing, two, three or four carbon atom.Although R 3and R 4all can be selected from hydrogen atom and alkyl (obtaining ammonium connexon), but typically R 3and R 4in one be lone-pair electron.Subscript n represent be at least 1 integer.In different embodiments, n accurately at least reaches or lower than such as 1,2,3,4,5,6,7,8,9,10,11 or 12, or the numeral between any two aforementioned value.Subscript m represent 0 or be at least 1 integer.In different embodiments, m accurately at least reaches or lower than such as 1,2,3,4,5,6,7,8,9,10,11 or 12, or the numeral between any two aforementioned value.In other embodiments, n and m sum is accurately or at least 1,2,3,4,5,6,7,8,9,10,11 or 12, or itself and in the scope of any two aforementioned value.
When Y is-O-or-S-group, R 2with the key between Y is covalent linkage or ionic linkage.If key is ionic linkage, then R 2be the organic or inorganic cation group of negative charge on balance Y, it is metal ion (such as, Na in this case +) or the carboxylate salt of ammonium ion (such as, ammonium ion, trimethyl ammonium ion or tetramethyl ammonium) or dithionate.In other embodiments, group-Y-R 2self can be positively charged ion, it must combine with anionic counterions (unlisted in formula 1), group-Y-R in this case 2expression-NR 3r 4r 5group, wherein R 3, R 4, and R 5be selected from hydrogen atom and/or alkyl.Monomer composition shown in formula (1) can contain other unlisted ionic portions.Any one or more ionic groups in formula (1) all can produce the salt of monomer composition.
In first group of embodiment of formula (1), monomer composition has the structure shown in following formula:
In second group of embodiment of formula (1), monomer composition has the structure shown in following formula:
In the 3rd group of embodiment of formula (1), monomer composition has the structure shown in following formula:
In the 4th group of embodiment of formula (1), monomer composition has the structure shown in following formula:
In the 5th group of embodiment of formula (1), monomer composition has the structure shown in following formula:
In the 6th group of embodiment of formula (1), monomer composition has the structure shown in following formula:
In the 7th group of embodiment of formula (1), monomer composition has the structure shown in following formula:
In the 8th group of embodiment of formula (1), monomer composition has the structure shown in following formula:
In the 9th group of embodiment of formula (1), monomer composition has the structure shown in following formula:
In the tenth group of embodiment of formula (1), monomer composition has the structure shown in following formula:
In the 11 group of embodiment of formula (1), monomer composition has the structure shown in following formula:
In formula (2)-(12), R 1, R 2, R 3, R 4, R 5, X, Y, n be identical with definition above with m, comprise above for any embodiment described in these groups or variable.And, for formula (8)-(10), if R 2, R 3, or R 4in one be lone-pair electron, then group-NR in any one in these structural formulas 2r 3r 4all can by-NR 2r 3replace.
For any one in above-mentioned formula (1)-(12), radicals R 2or-YR 2, particularly, can also be bio-related substance.Described bio-related substance can be such as derived from molecule or the macromole of organism, or the molecule of organism or macromolecular stand-in.Bio-related substance can such as target or regulate molecule, macromole or process in biomaterial or organism.Target spot can be the cytolemma of such as cell, organoid or cytoplasmic molecule.The object of target can be such as Function protein function or adjustment or regulate gene expression or other chemical substance (such as, medicine) that any position in the composition shown in target spot and formula (1) is contained is contacted.In different embodiments, R 2it is bio-related substance, it is or comprises such as peptide, dipeptides, tripeptides (such as, gsh), tetrapeptide, pentapeptide, six peptides, more senior oligopeptides, albumen, monose, disaccharides, trisaccharide, tetrose, more senior oligosaccharides, polysaccharide (such as, carbohydrate), core base, nucleosides (such as, adenosine, cytidine, uridine, guanosine, thymidine, inosine, and S-adenosylmethionine), Nucleotide (namely, single-, two-, or three-phos-phate forms), dinucleotides, trinucleotide, tetranucleotide, more senior oligonucleotide, nucleic acid (such as, DNA, sRNA, tRNA, mRNA, or plasmid), cofactor (such as, TPP, FAD, NAD, coenzyme A, vitamin H, Thioctamide, metal ion (such as, Mg 2+), metallic duster compound (such as, iron-sulfur cluster) or abiotic (that is, synthesize) target group.Some concrete protein types comprises enzyme, hormone, antibody (such as, monoclonal antibody), lectin and steroid.Antibody can be complete antibody, or remains the antibody fragment of antibody recognition part (that is, hypervariable region).Some example of antibody fragment comprises Fab, Fc and F (ab ') 2fragment.
The method be connected with other biological substance or non-biological material by biological substance is well known in the art.R 2or-YR 2biomaterial can be bonded to by direct reaction or by double reactive connexon.In order to biomaterial bonding, R 2or-YR 2for or comprise, or through suitably modifying to have, one or more group with one or more radical reactions of biomaterial.Such as ,-C (O) YR in formula (1) 2can Xuan Zi – COOH Huo – COOR 2group, wherein R 2be produce activation ester group (such as, succinimide or other active group), and react under the ester condition known in the art of the acid in formula (1) or activation with containing amino material (such as, peptide, albumen or nucleic acid), be connected to form acid amides with described material.In another example ,-the YR in formula (1) 2can be chlorine atom, this pattern (1) be acyl chlorides, and then it can with the substance reaction containing amino.In another example, R 2alkyl containing accessible reactive group (such as, wherein R can be selected from 2-(CH 2) n-R 2', wherein R 2' be reactive group and the same to the definition of n), wherein said reactive group can be such as hydroxyl, amino, thiol group, bromine atoms or atomic iodine.This type of reactive group any can be connected with the one or more active groups in biomaterial by known multiple double reactive connexon.Some double reactive connexon comprises amino-amino coupling (such as, the connexon of ester group with two activation), amino-mercaptan coupling (such as, at one end with the ester group of activation, and at the connexon of the other end with thiol-reactive group (such as, maleimide)), carboxyl-amino coupled, hydroxy-amino coupling, carboxyl-mercaptan coupling and mercaptan-mercaptan coupling.
In formula (1-12) in some embodiment any one, any one or more in following monomer composition can be excluded:
(i) the monomer composition according to formula (1), wherein X is NH, R 1for methyl, n be 3, m is 0, Y is O and R 2for H;
(ii) the monomer composition according to formula (1), wherein X is NH, R 1for methyl, n be 3, m is 0, Y is O and R 2for ethyl;
(iii) the monomer composition according to formula (1), wherein X is O, R 1for methyl, n be 1, m is 0, Y is O and R 2comprise adamantyl;
(iv) the monomer composition according to formula (1), wherein X is O, R 1for H, n be 1, m is 0, Y is O and R 2comprise adamantyl;
(v) the monomer composition according to formula (1), wherein X is O, R 1for H, n be 3, m is 1, Y is O and R 2for the tertiary butyl;
(vi) the monomer composition according to formula (1), wherein X is O, R 1for methyl, n be 1, m is 0, Y is O and R 2for methyl;
(vii) the monomer composition according to formula (1), wherein X is O, R 1for H, n be 1, m is 4, Y is O and R 2comprise the phenyl ring be connected with amylene oxide ring;
(viii) the monomer composition according to formula (1), wherein X is O, R 1for H, n be 1, m is 4, Y is O and R 2for hydroxyphenyl;
(ix) the monomer composition according to formula (1), wherein X is O, R 1for H, n be 1, m is 4, Y is O and R 2comprise the phenyl ring be connected with carboxycyclohexyl;
(x) the monomer composition according to formula (1), wherein X is O, R 1for H, n be 1, m is 0, Y is O and R 2comprise trimethylene oxide ring;
(xi) monomer composition according to formula (1), wherein X is O, R 1for H, n be 1, m is 0, Y is O and R 2for methyl;
(xii) monomer composition according to formula (1), wherein X is O, R 1for H, n be 1, m is 4, Y is O and R 2for (CH 2) 5cOOH;
(xiii) monomer composition according to formula (1), wherein X is O, R 1for H, n be 1, m is 0, Y is O and R 2for phenyl aldehyde base;
(xiv) monomer composition according to formula (1), wherein X is NH, R 1for H, n be 3, m is 0, Y is O and R 2for the tertiary butyl;
(xv) monomer composition according to formula (1), wherein X is O, R 1for methyl, n be 1, m is 4, Y is O and R 2for n-octyl; And
(xvi) monomer composition according to formula (1), wherein X is O, R 1for H, n be at least 1, m is 0, Y is O and R 2comprise N-succinimido.
In some embodiments, R 2, R 3, and R 4in one or more alkyl replaced by least one hydrophilic radical.Some example of hydrophilic radical comprises amino, imido grpup, acid amides, hydroxyl, ether, polyethers, carboxyl, ester (it can be inorganic ester, organic ester or thioesters), carbamate, urea groups, aldehyde radical, ketone group, vitriol, sulfonate, sulfone, sulfoxide, sulphite, phosphoric acid salt, phosphonate, phosphinate, phosphite, nitro, nitroso-group and charged group.In other embodiments, R 2, R 3, and R 4in at least one be alkyl only containing carbon and hydrogen atom, it or can also can not comprise one or more halogen atom.In another other embodiment, R 2, R 3, and R 4in at least one be the amphipathic group with hydrophobic parts and hydrophilic parts.Usually, the hydrophobic parts of amphipathic group contains at least three, four, five or six interconnective carbon atoms, only has hydrogen atom to be connected with described carbon atom.Other variable groups (that is, R 1and/or R 5) can also hydrophilic radical be comprised, or replace with and only comprise carbon and hydrogen, it or can also can not comprise one or more halogen atom, or replaces with amphipathic group.
In yet another aspect, the present invention relates to the polymkeric substance comprising any monomer composition adduction unit mentioned above.According to the understanding of this area, preparation " adduction unit " refer to described in the application containing the polymerization being repeated by polyethylene carbon atom under poly monomer composition condition known in the art to connect.In one group of embodiment, polymkeric substance is the homopolymer only having the monomer structure of a type to build, and it is selected from any monomer structure mentioned above.In another group embodiment, described polymkeric substance is multipolymer, its can be such as binary, ternary or the multipolymer of quaternary.And multipolymer can have any known arrangement mode, as block, at random, replace and grafting arrangement.In one group of embodiment, multipolymer is only built by two or more monomer compositions mentioned above.In other embodiments, multipolymer is built by least one monomer composition mentioned above and the monomer composition that do not describe above.Some example can introducing other monomer composition of copolymer compositions comprises any material containing vinyl that can carry out addition reaction, as vinylformic acid, methacrylic acid, and alkyl ester derivatives (such as, methacrylic ester, ethyl propylene acid esters, n-propyl acrylate, methyl methacrylate, β-dimethyl-aminoethylmethacrylate, positive n propyl methacrylate), acrylamide and N-or N thereof, N-alkyl derivative (such as, N methacrylamide, N, N-DMAA, N-ethyl acrylamide, N, N-acrylamide, N-butylacrylamide), vinylbenzene, 4-Vinyl phenol, to vinyl benzoic acid, and vinyl acetate.Other monomer can also containing for carrying out structural modification or being connected to the reactive group of other group or chemical entities further.Some example of reactive group comprises carboxyl, carboxyl ester, amino, haloalkyl, cyclic ethers and contains mercapto groups.
Polymkeric substance mentioned above can be described easily by following formula:
In formula (13), X, Y, n, m, R 1, and R 2all identical with definition above.Variable p be at least preferably 10(namely, at least 10 monomeric units).In some embodiments, p can be at least 20,50,100,500 or 1000.In other embodiments, p corresponds to the weight-average molecular weight (M of polymkeric substance w), such as M wbe at least 1000,5000,10,000,50,000,100,000 or higher.The polymkeric substance of formula (13) is in the embodiment of homopolymer wherein, and polymkeric substance only contains the repeating unit of the type shown in good grounds formula (13), wherein variable X, Y, n, m, R between each unit 1, and R 2identical.Polymkeric substance wherein in formula (13) is in one group of embodiment of multipolymer, and described multipolymer is only built by the p monomeric unit described in formula (13), and condition is between each unit, variable X, Y, n, m, R 1, and R 2in at least one different from other.Polymkeric substance wherein in formula (13) represents in another group embodiment of multipolymer, and any amount of monomeric unit do not described in the p monomeric unit of described multipolymer described by formula (13) and formula (13) builds.Or, multipolymer can be described as that there is the different monomeric unit of p1 with p2 (for copolymer), or the monomeric unit that p1, p2 are different with p3 (for terpolymer), wherein should understand p1 and p2 sum, or p1, p2 and p3 sum is p.Polymkeric substance can have any suitable polydispersity value, as or lower than 2,1.5,1.4,1.3,1.2 or 1.1 value, or be or higher than 1,1.2,1.5,1.7 or 2 value.
In first group of embodiment, the polymkeric substance according to formula (13) has the structure shown in following formula:
In second group of embodiment, the polymkeric substance according to formula (13) has the structure shown in following formula:
In the 3rd group of embodiment, the polymkeric substance according to formula (13) has the structure shown in following formula:
In the 4th group of embodiment, the polymkeric substance according to formula (13) has the structure shown in following formula:
In the 5th group of embodiment, the polymkeric substance according to formula (13) has the structure shown in following formula:
In formula (13)-(18), R 1, R 2, R 3, R 4, R 5, X, Y, n, m and p definition same as above, comprise any embodiment for these groups or variable mentioned above.And any one or more eliminatings for monomer composition mentioned above are also applicable to any polymer composition mentioned above.
In some embodiments, its formula of (13) represents containing at least two the dissimilar monomeric units being selected from any monomer composition (that is, formula 1-12) mentioned above, at the m-YR of each unit 2or R 2in at least one constitutional features different from other.In these embodiments, Y can be identical or different between dissimilar monomeric unit, and R 2can be identical or different independently between dissimilar monomeric unit.In an embodiment specifically organized, the R that the part in monomeric unit has 2for H, and the R that the part in monomeric unit has 2for alkyl.Such as ,-YR 2can represent that in monomeric unit, a part of – OH(is namely, carboxy blocking group), Yi is Ji – YR 2ke Yi Biao Shi – OR 2group, wherein R 2be the alkyl of another part in monomeric unit (namely, the capping group of carboxyl ester), wherein said alkyl be such as have at least one, the straight or branched alkane of two or three carbon atoms and four, five, six, seven, eight, nine, ten, 11 or 12 carbon atoms at the most.In previous example, it is S or-NR that same principle is applicable to wherein Y 3r 4, or wherein different monomers unit has the situation of different Y group.-the YR that the part that some other example of multipolymer comprises wherein monomeric unit has 2wei – OR 2(wherein R 2for H or alkyl), and-the YR that another part of monomeric unit has 2wei – SR 2or-NR 3r 4r 5situation.In another example of multipolymer ,-the YR that the part of monomeric unit has 2ke Yi Wei – SR 2(wherein R 2for H or alkyl), and-the YR that another part of monomeric unit has 2for-NR 3r 4r 5.In any aforesaid embodiment, the amount (that is, there is the monomer of higher quantity) of a part of monomeric unit can higher than another part monomeric unit.
In a specific embodiment, the polymkeric substance according to formula (13) is the amide group copolymer derivative of polymkeric substance shown in formula (14).In this embodiment, part O-R in following polymkeric substance (or multipolymer) 2group (that is, one or more):
By one or more amino group (and ， – NR 3r 4r 5group) substitute, thus obtain wherein at least partly monomeric unit there is the polymer derivant of following chemical structure:
(that is, *-(formula)-* is equivalent to-(formula) the continuous key that double asterisk in formula (19) represents in polymer backbone structure r-, wherein r is at least 1).Double asterisk comprises the possibility that the monomeric unit shown in single monomeric unit through type (14) shown in formula (19) is connected with the side of each asterisk.In previous example, the multipolymer of amide group base derivatize can contain an amide group monomer in whole polymkeric substance, or can contain more than one or multiple amide group monomeric unit, wherein at least one amino unit has the character that the monomeric unit shown in through type (14) is connected with each asterisk side.Double asterisk also comprises the monomeric unit shown in one group of formula (19) (such as, monomeric unit shown at least 2,3,4,5,6,7,8,9 or 10 formulas (19), or the p monomeric unit shown in some formulas (19)) possibility that is connected with each asterisk side of the monomeric unit shown in through type (14) or one group of monomeric unit.
In another group embodiment, the polymkeric substance according to formula (13) is the amide group copolymer derivative of sulfydryl polymkeric substance shown in formula (15), the amido polymer derivative all fours shown in itself and formula mentioned above (14).In this embodiment, the part S-R in the polymkeric substance (or multipolymer) shown in formula (15) 2group is by one or more amide group (that is ,-NR 3r 4r 5group) substitute, thus obtain wherein at least partly monomeric unit there is the polymer derivant of structure shown in formula (19).
In another group of embodiment, the polymkeric substance according to formula (13) is the sulfydryl copolymer derivative of carboxyl polymer shown in formula (14), the amido polymer derivative all fours shown in itself and formula mentioned above (14).In this embodiment, the part O-R in the polymkeric substance (or multipolymer) shown in formula (14) 2group is by one or more mercapto groups (that is, S-R 2group) substitute, thus obtain wherein at least partly monomeric unit there is the polymer derivant of following formula structure:
In formula (20), X, R 1, R 2, n and m definition same as above.Double asterisk with above for described in formula (19), there is identical meanings.
In yet another aspect, the present invention relates to and a kind ofly produce polymkeric substance mentioned above and the method for multipolymer.Any method by vinyl group coupling addition polymerization well known in the art is all applicable to the present invention.These class methods are well known in the art.The method can use strict chemical process, strict physical method (such as, UV photodissociation or ionizing rays) or its combination.Some example of known polymerization process comprises anionoid polymerization, cationoid polymerisation, emulsion polymerization, the mass polymerization of chain growth polymerization (such as, radical polymerization) and these processes or living polymerization.
In certain embodiments, polymerization process is atom transfer radical polymerization (ATRP), and it is living polymerization type well known in the art.In ATRP, there is ATRP catalyzer (typically being transiting state metal catalyzer, as Cu(I) compound) and ATRP inhibitor (typically being haloalkane) when, under monomer composition being placed in radical polymerization condition.The peculiar advantage of ATRP can provide uniform polymer chain to increase (that is, heterogeneity index is lower) for it.Other form such as reverse ATRP, AGET ATRP and the ICAR ATRP of ATRP are also applicable to the present invention.
In other embodiments, polymerization process is reversible addion-fragmentation chain transfer (RAFT) polymerization, a kind of controlled radical polymerization process.RAFT relies on its polymerization validity in monomer composition widely to have peculiar advantage in the preparation of rapid hardening polymkeric substance.And RAFT can produce the polymkeric substance of the specified molecular weight with low-down heterogeneity index.RAFT can also produce the polymkeric substance with high complexity structure, as pectination, brush, starlike and branch-shape polymer.
In addition to the monomer, RAFT reaction generally also needs radical initiator, chain-transfer agent and solvent.Described initiator can be any initiator well known in the art, but be more typically the initiator containing azo, as Diisopropyl azodicarboxylate (namely, AIBN) or 4,4 '-azo two (4-cyano group valeric acid) (that is, ACVA), be equivalent to 4,4 '-azo two (4-cyanopentanoic acid) (that is, A-CPA), or its combination.Described chain-transfer agent typically is thiocarbonylthio compound (that is, the compound of Han You – C (=S) S-group).Described thiocarbonylthio compound can be dithioesters, trithiocarbonate or dithio carbamate compounds.Usually, thio-carbonyl sulfide reagent comprises the strong electronegative group (such as, prussiate or carboxylic acid) adjacent with thiocarbonyl thio group, to realize the function of part transfer agent as homolysis leavings group.General often kind of chain-transfer agent all can produce different polymerization results to various types of monomer, and the effect of some chain-transfer agent to the monomer of object type and polymkeric substance is obviously not so good as other.Therefore, general needs carefully select chain-transfer agent, to guarantee that its combination that can make specific monomer and monomer produces effective polymerization.Some example of dithioesters chain-transfer agent comprises 4-cyano group-4-(thiobenzoyl sulphur) valeric acid and 2-cyano group third-2-base-Thiobenzoate.Some example of trithiocarbonate chain transfer agent comprises 2-methyl-2-[(dodecyl sulphate base thiocarbonyl) alkylsulfonyl] propionic acid, 4-cyano group-4-(dodecyl sulphate base thiocarbonyl) alkylsulfonyl valeric acid, S-cyano methyl-S-dodecyl trithiocarbonate, S-(2-cyanopropyl-2-base)-S-dodecyl trithiocarbonate and S, S-phenylbenzene trithiocarbonate.The example of dithiocarbamate chain-transfer agent is 2-cyanomethyl-N-methyl-N-phenyl dithiocarbamate.
RAFT reaction can at room temperature (that is, about 15,20,25 or 30 ° of C, or within the scope of this), or at elevated temperatures (such as, 40,45,50,55,60,65,70,75 or 80 ° of C, or within the scope of this) carry out.In different embodiments, RAFT reaction be carry out in organic or aqueous solution batch, emulsification or suspendible reaction.In RAFT reaction, in polymer growth process and in the final polymer, the part of chain-transfer agent fracture is still retained in the end of polymkeric substance.
The method of producing polymkeric substance may further include the chemical modification step of initial polymer product.Such as, any suitable amide condensed reagent well known in the art and reaction can be used, prepare the amide group copolymer derivative of polymkeric substance shown in formula (14) mentioned above or (15).Some suitable amidation reagent comprises carbodiimide (such as, EDC and DCC), NHS, 1-hydroxyl-7-azepine benzotriazole and hydroxybenzotriazole, and combination (such as, EDC and NHS).In a specific embodiment, amide condensed reagent is 4-(4,6-dimethoxy-1,3,5-triazines base-2-base)-4-methylmorpholinium chloride (DMTMM).For the sulfydryl copolymer derivative of the carboxyl polymer shown in preparation formula (14), suitable thia agent can be used, as lawesson reagent.For modifying the copolymer derivative of polymkeric substance shown in formula (14), work as R 2for H(is, polymkeric substance contains carboxylic acid-terminated group) time by using hydrocarbyl replaces carboxylic acid H atom, can esterification be used, as utilized the reaction of ethanol under condensation condition, or Carboxylic Acid become Acetyl Chloride 98Min. again with ethanol synthesis, or with alkyl halide compound generation alkylated reaction.
In yet another aspect, the present invention relates to combination of polymers library mentioned above.According to further describing of appended embodiment, composition libraries is produced preferably by extensive combinatorial compound method.X, Y, R is selected from polymkeric substance in combinatorial library 1, R 2, n, m and p any one or more variablees can change (normally systematic change).Polymkeric substance can also change according to the amount of group derivatize in multipolymer (that is, replacing), or in other words, according to relative populations or the weight ratio of dissimilar monomeric unit.Polymkeric substance library can especially for carrying out the object of high flux screening to polymkeric substance, to determine that change in a series of polymkeric substance is on the impact of its LCST character.In order to this object, generally combinatorial library is stored in or is transferred in the orifice plate being widely used in combinatory analysis and clinical diagnosis (that is, microtitration or microwell plate).Orifice plate can hold such as 6,12,24,48,96,384 or 1536 sample wells, and it can also be corresponding with the quantity of testing compound.Appropriate polymkeric substance can be held, typically in suitable solvent in each hole.Each hole typically has and is no more than 1mL, 500 μ L, 200 μ L, 100 μ L, 50 μ L, 10 μ L, 1 μ L, 500nL, 200nL or 100nL volume.
By using combination of polymers library, and carry out high throughput analysis to it subsequently, the number of polymers that one or more characteristics of variables systematicness changes can for its LCST character by Effective selection.And character data can be compiled into database, and data are processed with the relation between analytic structure and character.At least one Core Superiority of this type of combined method is that the dependency between its structure-property is very useful in the properties of prediction following supposition LCST polymkeric substance.
Hereinafter provide the object of embodiment for illustrating and describing optimal mode of the present invention.But the embodiment listed can not be limited protection scope of the present invention by any mode herein.
Embodiment 1
The synthesis of carboxylic acid-capping monomer (CTMAAm)
The synthetic route of CTMAAm monomer is as shown in Fig. 1 (A).
First, in the basic conditions tertiary butyl 12-amino-4,7,10-trioxa dodecylate (i) react with methacrylic chloride generate the N-(tertiary butyl 3,6,9-trioxa-12-decylate) Methacrylamide (ii).The details that compound (ii) synthesizes is as follows: pass into N at 0 ° of C 2condition under by amino for tertiary butyl 12--4,7,10-trioxa dodecylate (i) (300mg, 0.865mmol) and triethylamine (0.15mL, 1.08mmol) at anhydrous CH 2cl 2(10mL) dissolve 15 minutes in.The anhydrous CH of 5mL will be dissolved in 2cl 2methacrylic chloride (0.11mL, 1.08mmol) drop in mixture, under 0 ° of C stir 1 hour, at room temperature stir 2 hours again.Make use NaHCO 3diluted reaction mixture also uses CH 2cl 2extraction.Wash organic phase three times with water and use MgSO 4carry out drying.At reduced pressure conditions solution filtered and concentrate, obtaining the yellow oil of thickness.By flash chromatography (hexane/ethyl acetate 1:5), purifying is carried out to residue, to obtain colorless oil (ii), (292mg, 80%). 1H NMR（DMSO-d 6）：δ1.40（s,9H）、δ1.84（s,3H）、δ2.41（m,2H）、δ3.26（m,2H）、δ3.44（m,2H）、δ3.50（m,8H）、δ3.58（s,2H）、δ5.32（s,1H）、δ5.65（s,1H）、δ7.94（s,2H）。Ultimate analysis: calculated value (C 17h 31nO 6): C, 59.11%; H, 9.05%; N, 4.05%.Measured value: C, 58.79%; H, 8.97%; N, 4.14%.
Secondly, by using trifluoroacetic acid (TFA) to (ii) going protection, use Amberlyst A-21 process to prepare CTMAAm(iii to remove remaining TFA subsequently).The details that compound (iii) synthesizes is as follows: by CH 2cl 2(1mL) add with the mixture of trifluoroacetic acid (TFA, 1mL) the 200mgN-(tertiary butyl 3,6, the 9-trioxa-12-decylate being placed in 50mL round-bottomed flask) Methacrylamide (ii) in.Stir at ambient temperature after 30 minutes, volatile removed in vacuo.Oiliness residue is dissolved in the anhydrous CH of 30mL 2cl 2in and use 1g Amberlyst A-21 plastic resin treatment.After stirring 1 hour at ambient temperature, solids removed by filtration, solvent removed in vacuo.By flash chromatography (hexane/methanol/ethyl acetate 1:0.5:20), purifying is carried out to residue, to obtain N-(12-carboxyl-3,6,9-trioxa) Methacrylamide (iii, 113mg, 57%). 1HNMR（DMSO-d 6）：δ1.83（s,3H）、δ2.43（m,2H）、δ3.26（m,2H）、δ3.43（m,2H）、δ3.50（m,8H）、δ3.58（s,2H）、δ5.32（s,1H）、δ5.64（s,1H）、δ7.94（s,2H）。
Embodiment 2
The polymerization of CTMAAm is to form brush-type polymkeric substance (pCTMAAm)
The synthetic route of pCTMAAm monomer is also as shown in Fig. 1 (A).
Generally speaking, the RAFT of CTMAAm is polymerized and carries out in methyl alcohol in 60 ° of C, and use 4-cyanopentanoic acid dithiobenzoic acid ester (iv) as chain-transfer agent (CTA) and 4,4 '-azo pair (4-cyanopentanoic acid) is (v) as radical initiator (I).(vi), as shown in Fig. 1 (B), it contains the polyoxyethylene glycol oligomer with C-terminal to end product poly-[N-(12-carboxyl-3,6,9-trioxa) Methacrylamide] (pCTMAAm), and it is all easily molten in multi-solvents.
By RAFT to the polymerization synthetic polymer of CTMAAm more detailed building-up process (vi) as shown below.Before the experiments, by least degasification 10 minutes under a nitrogen of all liquid reagent.Use respective solvent to prepare radical initiator 4 respectively, 4 '-azo two (4-cyanopentanoic acid) (A-CPA) (iv) with 4-cyanopentanoic acid dithiobenzoic acid ester (that is, CTA or CPA-DB) storing solution (v), to guarantee reactant ratio accurately.The exemplary of polymerization is as follows: by iii(56.38mg, 0.244mmol) and CPA-DB(0.247mg, be 8.9 × 10 in 122 μ L methyl alcohol -4mmol) 1mL is transferred to passing into nitrogen five minutes in the ampoule of magnetic stirring apparatus.Then by A-CPA(0.062mg, be 2.2 × 10 in 30 μ L methyl alcohol -4mmol) add in ampoule and also pass into nitrogen again two minutes.Use oxygen flame by ampoule sealing and immersed with continuous stirring in 60 ° of C oil baths.By cooling ampoule termination reaction on ice bath after 48 hours, then solution is exposed in air.Being undertaken precipitating by adding a large amount of diethyl ether under agitation, to filter and dried in vacuo overnight obtains polymer poly [N-(12-carboxyl-3,6,9-trioxa) Methacrylamide] (pCTMAAm) (vi).Spectra/Pro regenerated cellulose dialysis tubing (3.5kDa MWCO) is used to utilize deionized water to exchange dialysis three days to be further purified polymkeric substance and lyophilized 2 days.GPC is utilized to calculate the M of this sample nbe respectively 46,100Da and 1.07 with PDI, utilizing gravimetry estimation to obtain conversion percentage is 87%. 1H NMR（400MHz,D 2O,ppm）：δ0.92（brs,3H）、δ1.65（brs,2H）、δ2.67（m,2H）、δ3.32（m,2H）、δ3.58（m,2H）、δ3.68（m,8H）、δ3.80（s,2H）、δ7.71（s,2H）。
Use different monomer starting point concentrations ([M] 0) and different [M] 0/ [CTA] 0ratio prepares some pCTMAAm polymkeric substance, but [CTA] 0/ [I] 0ratio keep constant (1:0.25), as shown in table 1 below.Because in this system, iv has effective RAFT ability and the right coordination of monomer-initiator, thus obtain well-defined pCTMAAm polymkeric substance, these polymkeric substance have the different molecular weight consistent with theoretical molecular and very narrow polymolecularity (PDI=1.05-1.09).By regulating [M] 0/ [CTA] 0ratio, 10100 to as high as the molecular-weight average (M obtaining several pCTMAAm in 84300 scopes n), this with at identical [M] 0(1.5mol L under condition -1) theoretical M nunanimously.These results are consistent with controlled RAFT polymerization behavior.Except [CTA] 0time extremely low beyond yield lower (53%), the yield of polyreaction is higher (~ 80-90%).To three different [M] 0(1.0,1.5 and 2.0mol L -1) find more afterwards, [M] 0pDI is not significantly affected, at [M] 0for 2.0mol L -1time obtain the highest transformation efficiency and M n.
Table 1: the PAFT polymerization of pCTMAAm under differential responses condition
agPC is utilized to measure. butilize gravimetric analysis. caccording to previously described (Brouwer, H.D., et al., J.Polym.Sci.Polym.Chem.Ed., 38,3596-3603 (2000); Pelet, J.M., et al., Macromolecules, 42,1494-1499 (2009)) calculate M n(theoretical value).
The solubleness of pCTMAAm polymkeric substance in different solvents sees the following form 2.
The solubleness of table 2:pCTMAAm polymkeric substance in different solvents
S, solvable (concentration at least reaches 20gL); SS, slightly soluble; I, insoluble.
For identifying the control/activity characteristic of the RAFT polymerization of CTMAAm, to monomer conversion and polymkeric substance M nbe studied with the dependency of PDI.In methyl alcohol and [M] 0=1.5mol L -1under condition, within continuous 4,8,12,18,24,36 and 48 hours, carry out a series of RAFT polymerization ([M] 0/ [CTA] 0/ [I] 0=200:1:0.25).As shown in Figure 2 (A) shows, in polymerization process, M nand M (GPC) nthe degree of fitting of (theoretical value) is fine, substantially has linear.When transformation efficiency is lower, PDI is relatively high, but along with M nincrease its be down to 1.06 by 1.31 because reach gradually chain tra nsfer balance.By comparing 200:1:0.25,150:1:0.25 and 200:1:0.1(Fig. 2 B) find, change [M] 0/ [CTA] 0/ [I] 0reactant ratio, three polyreactions linearly change in time.Research finds under all polymerizing conditions, and when incubation time shorter (about 2 hours), RAFT is polymerized to pseudo-first order kinetics.At identical [CTA] 0/ [I] 0under ratio, [M] 0/ [CTA] 0reducing causes percent polymerization to increase, because the relative concentration of CTA active substance is higher.But the concentration of radical initiator reduces by 2.5 times and does not have a significant effect to percent polymerization.
The result display of solubleness assessment, pCTMAAm all easily molten (being defined as >20g/L), comprises water, methyl alcohol, ethanol, DMSO and DMF in multi-solvents.In addition, the result display that dynamic light scattering detects, polymkeric substance all has the conformation of expansion in all kinds of SOLVENTS, points out the C-terminal of its side chain to be easy to close in synthesis.Use three kinds of model part agmatines (positively charged ion), GalN (polyvalent alcohol) and hexylamine (hydrophobicity) and DMTMM as condensing agent, determine the functionalization characteristic of pCTMAAm.Various ligand classes to be all easy to accept by the carboxylic group of pCTMAAm.When target is substituted by 100%, the replacement yield of each part is more than 80%.Especially, the yield of agmatine is that 83%(reacts in water), the yield of GalN is that 80%(reacts in water) and the yield of hexylamine be that 94%(reacts in methyl alcohol) and 82%(react in DMSO).As comparing, agmatine, GalN and hexylamine are replaced to poly-(methacrylic acid) with same molecular amount, result all obtains insoluble product under all reaction conditionss, shows that the oligomer ethylene oxide side chains of pCTMAAm also has solublization in multi-solvents.
So just the new precursor for the synthesis of functional biological materials storehouse is described.Be easy to make monomer polymerization by RAFT polymerization, and it has narrower PDI and controlled molecular weight.Particularly, pCTMAAm have band C-terminal side chain, it is easy to be functionalized in protic and aprotic solvent, can leniently replace by several functions group, add the potential diversity in polymkeric substance library.
Embodiment 3
Be that template obtains polymerization mix storehouse by derivatize with pCTMAAm
The polymkeric substance that exploitation has specific lower critical solution temperature (LCST) depends on empirical method to a great extent.Because empirical method is based on test and mistake substantially, and when determining polymer property, have a different set of variable to work, in this way significant discomfort for finding the LCST polymkeric substance with special properties.Therefore, instant work in combination is devised to attempt to find to have by a kind of more direct mode the polymkeric substance of specific LCST characteristic.Especially, one or more structure variables of the LCST polymkeric substance systematically changed described in the application are made every effort in instant research, to produce the storehouse of this base polymer, and are detected polymkeric substance library by high flux screening method.And, in the data importing database that this type of research can be obtained, to data analysis to resolve the dependency between its structure-property, the then forecasting tool of the LCST character of its polymkeric substance can also do not detected as prediction.
In the exemplary research that the application describes in detail, the storehouse be made up of 45 LCST polymkeric substance is studied.Change following variable and prepare 45 LCST polymkeric substance: the molecular weight of polymkeric substance, terminated hydrophobic substituting group are (that is, at R 2) size and polymkeric substance in the substitution value of hydrophobic group (that is, by Initial R that alkyl replaces 2the relative populations of group).The parallel polymkeric substance prepared in polymkeric substance library under equal reaction conditions, to prevent the unexpected textural difference because preparation condition difference causes.Syntheti c route refers to Fig. 3, introduces pCTMAAm(and has carboxylic acid-terminated group, be i.e. wherein-OR 2for-OH) as polymer precursor, use 4-(4,6-dimethoxy-1,3,5-triazines base-2-base)-4-methylmorpholinium chloride (DMTMM) as catalyzer, on pCTMAAm, connect different alkyl groups by the condensation reaction of gentleness.As shown in Figure 3, the polymkeric substance of connection is multipolymer, and it contains x the monomeric unit derived from initial pCTMAAm polymkeric substance, and the OH base wherein on pCTMAAm blocked with polymer hydroxy-acid group is by amino group (-NHR, wherein R and R 2there is identical meanings) y the monomeric unit of replacing.Therefore, the multipolymer replaced contains carboxylic acid-terminated group (it is hydrophilic substantially) and N-replaces capped with carboxamide group (C (O) NHR), wherein R is alkyl, its amount of carbon atom be variable (especially, n-propyl, normal-butyl and n-hexyl), it is hydrophobic substantially.Sum up according to following table 3, also change three different molecular weight, and some substitution levels.
Table 3: the constitutional features changed in LCST polymkeric substance
Before proceeding, three kinds of pCTMAAm polymkeric substance that preparation has different molecular weight (according to what sum up in table 3) are polymerized, to make it have extremely low PDI(<1.15 according to method mentioned above by RAFT).Below connect and easily complete: before adding alkylamine, by pCTMAAm and 4-(4,6-dimethoxy-1,3,5-triazinyl-2-base)-4-methylmorpholinium chloride (DMTMM) is dissolved in methyl alcohol, [COOH in pCTMAAm]: [DMTMM]: [alkylamine (RNH 2) in NH 2] there is specific mol ratio, and the starting point concentration of pCTMAAm is 20mg/mL.Introduce DMTMM, as condensing agent, carboxyl and amido coupling are formed amine, because it has high solubleness in water and ethanol, and no coupling product.At room temperature stir after 18 hours, removed methanol under vacuum obtains modified LCST polymkeric substance.Make [DMTMM]: [NH in alkylamine 2] ratio keep 1:1, to make amino group, there is identical activity.By regulating [COOH in pCTMAAm]: [NH in alkylamine 2] reactive ratio obtain there is the LCST polymkeric substance of different Replacement rate between 23%-90%.For being further purified the product of connection, product is soluble in water, and exchange dialysis three days with deionized water, change three deionized waters every day, then freeze-drying two days.Utilize this method of relatively easily accomplishing, generally can prepare complete polymkeric substance library in one week.
Once prepare polymkeric substance library, then carry out the detection of LCST high flux screening according to following step: by each polymer dissolution in storehouse in deionization (DI) water, its concentration is made to be 3mg/mL, transfer them in 96-orifice plate with the volume of every hole 200 μ L, in 2 ° C to 90 ° C continuous temperature transition range, then use in 500nm place microplate reader to detect it.The result of LCST represents hygrogram with transmissivity, sees Fig. 4.As shown in Figure 4, in polymkeric substance library, observed the wide region LCST of 4 ° of C to 85 ° of C.LCST is defined as the mid point of temperature-change curve.The sharp transition that each sample demonstrates shows that these polymkeric substance have significant temperature sensitivity.Three times are repeated to the detection of LCST, with the repeatability of verification msg.The LCST carried out in the application detects and generally completed in about one or two day.
LCST and three structural parameter (molecular weight of template polymer, be connected alkyl group length and connect substitution value) between relation see Fig. 5 A-5C.As shown in figures 5a-5c, no matter linking group is propyl group, butyl or hexyl, and the LCST with the polymkeric substance of same molecular amount is almost linear reduction along with the increase of Connected degree demonstrates.Can believe its reason be polymer system hydrophobicity with connect substitution value increase and increase.Hydrophobic increase makes polymkeric substance reach between amide group that hydrophilic-hydrophobic interaction stagnation point needs to overcome and water molecules, and the energy of hydrogen bond reduces.Also as shown in figures 5a-5c, when substitution value is identical, the molecular weight of polymkeric substance is higher, and its LCST is lower, and it sees the situation that end-blocking alkyl is propyl group, butyl or hexyl.Can believe and cause the reason of the latter's effect to be the trend that ability that polymkeric substance that molecular weight is higher himself freely stretches has reduction, and it has self assemble to form the trend (generally show as when temperature is lower and produce solid sediment in the solution) of spherule.As Fig. 5 A-5C further shown in, when molecular weight and substitution value are constant, at propyl group (3 carbon), butyl (4 carbon), between hexyl (6 carbon), polymkeric substance demonstrates the LCST of reduction along with the growth connecting long alkyl chains.Can believe and cause the reason of the latter's effect to be that chain-like alkyl increases the ability increase making polymkeric substance reach phase in version at a lower temperature, thus corresponding to the general trend that LCST reduces along with the increase of long alkyl chains.And, regardless of the molecular weight of template polymer, at propyl group, butyl, between hexyl, three substitution value dependency LSCT slope of a curves increase with the increase connecting alkyl carbon atoms quantity, its show to connect substitution value identical time, alkyl chain is longer, and it is larger on the impact of polymkeric substance LCST.
As shown in figures 6 a-c, in linking group, no matter whether there is propyl group, butyl or hexyl replace, the pH value of polymers soln raises along with the increase connecting substitution value.Can believe and cause the reason of the latter's effect to be increase gradually along with being connected with hydrophobicity NHR group, carboxyl stable in polymkeric substance-carboxyl interaction of hydrogen bond reduces.Also, as shown in figures 6 a-c, when connecting substitution value and being identical, at propyl group, butyl, between hexyl, pH value raises with the increase connecting alkyl length.Such as, when substitution value is 60%, the pH value of propyl group, butyl and hexyl series is about 4.25,4.5 and 5.5 respectively.Can believe and cause the reason of the latter's effect to be along with the length of end-blocking R group increases, carboxyl stable in polymkeric substance-carboxyl interaction of hydrogen bond reduces (also because its hydrophobicity-hydrophobic interaction increases when the length of R group increases).As illustrated in the drawing, these LCST are pH-sensitive substantially.
Based on the data obtained from the storehouse be made up of 45 polymkeric substance, depict the three-phase LCST polymkeric substance figure with three parameters, comprise the carbonatoms of the molecular weight of template polymer, substitution value and linking group.This three phase diagram is shown in Fig. 7.OriginPro8.0 is used to be normalized data, to be fitted to leg-of-mutton phasor.In order to adjust polymkeric substance heart distribution in the drawings, the data as substitution value are the percentage of raw data; Data as linking group carbonatoms are ten times of exact amount; And the data being used as polymericular weight are the thousandth of exact amount.
With the carbonatoms of the molecular weight of three considerations things, linking group and substitution value for coordinate determines the position of polymkeric substance in the three phase diagram shown in Fig. 7.The LCST of polymkeric substance becomes possibility to utilize Fig. 7 that prediction is supposed, by will supposition polymkeric substance structural parameter input program and observe its position relative to each known LCST value.Such as, if the molecular weight of template polymer is 60x10 3, linking group carbonatoms be 5 and substitution value be 40%, then the normalization data of these three axles is respectively 0.4,0.33 and 0.27.The LCST polymkeric substance of the supposition of the position display in Fig. 7 shown in arrow falls into figure.Therefore, three phase diagram can as finding the very useful forecasting tool with the new LCST polymkeric substance of specific LCST value and other peculiar property.
Raw data for drawing the three phase diagram shown in Fig. 7 is listed in the table below in 4.
Table 4: for drawing the raw data of the three phase diagram shown in Fig. 7
Of the present inventionly to think at present preferred embodiment although shown and described, in the scope that the claim of enclosing in the present invention defines, those skilled in the art still can carry out multiple change and amendment.

Claims (30)

1. the monomer composition represented with following chemical structure:
Wherein R 1be selected from hydrogen atom or the alkyl containing at least one carbon atom; R 2be selected from the alkyl containing at least one carbon atom; X represents-NR 5-group, and Y Biao Shi – NR 3r 4-group, wherein R 3, R 4, and R 5represent hydrogen atom or the alkyl containing at least one carbon atom independently, in addition, R 3and R 4in one can represent lone-pair electron; Subscript n represents the integer of 1-12; And subscript m represents the integer of 1-12; Wherein said alkyl independently and optionally by least one heteroatoms or heteroatom group replace; Wherein R 2biological substance can be comprised alternatively.
2. monomer composition according to claim 1, wherein R 1hydrogen atom or methyl group.
3. monomer composition according to claim 1, wherein R 2, R 3and R 4in at least one alkyl replaced by least one hydrophilic radical.
4. monomer composition according to claim 3, at least one wherein said hydrophilic radical is selected from lower group: amino, imino-, amide group, hydroxyl, ether, polyethers, carboxyl, ester, carbamate, urea groups, aldehyde radical, ketone group, vitriol, sulfonate, sulfone, sulfoxide, sulphite, phosphoric acid salt, phosphonate, phosphinate, phosphite, nitro, nitroso-group.
5. monomer composition according to claim 1, wherein R 2, R 3and R 4in at least one be alkyl, described alkyl is only containing carbon atom and hydrogen atom, and optionally one or more halogen atom.
6. monomer composition according to claim 5, wherein said alkyl contains at least two carbon atoms.
7. monomer composition according to claim 5, wherein said alkyl contains at least three carbon atoms.
8. monomer composition according to claim 1, wherein R 2, R 3and R 4in at least one be amphipathic group containing hydrophobic parts and hydrophilic parts.
9. monomer composition according to claim 8, wherein said amphipathic group comprises the hydrophobicity connection portion by least one hydrophilic radical end-blocking.
10. the copolymer compositions represented with following chemical structure:
Wherein R 1be selected from hydrogen atom or the alkyl containing at least one carbon atom; R 2it is hydrogen atom; X represents-O-or-NR 5-group, and Y represents-O-group, wherein R 5represent hydrogen atom or the alkyl containing at least one carbon atom; Subscript n represents it is the integer of 1-12; Subscript m represents it is the integer of 1-12; And subscript p represent be at least 2 integer; Wherein said alkyl independently and optionally by least one heteroatoms or heteroatom group replace;
O-R wherein in above-mentioned formula (13) 2radical moiety is replaced by amino group, thus obtains copolymer derivative, and wherein monomeric unit has following chemical structure at least partially:
Wherein R 1and R 2as defined above, R 1be selected from hydrogen atom or the alkyl containing at least one carbon atom, R 2hydrogen atom, R 3the alkyl containing at least one carbon atom, R 4represent lone-pair electron; X represents-O-or-NR 5-group, wherein R 5represent hydrogen atom or the alkyl containing at least one carbon atom; Subscript n represents it is the integer of 1-12; Subscript m represents it is the integer of 1-12; Wherein said alkyl independently and optionally by least one heteroatoms or heteroatom group replace.
11. copolymer compositions according to claim 10, wherein p is at least 10.
12. copolymer compositions according to claim 10, wherein n is 2-12.
13. copolymer compositions according to claim 10, wherein n is 3-12.
14. copolymer compositions according to claim 10, the weight-average molecular weight of wherein said multipolymer is at least 1,000.
15. copolymer compositions according to claim 10, the polydispersity value of wherein said multipolymer is greater than 2.
16. copolymer compositions according to claim 10, the polydispersity value of wherein said multipolymer is less than 1.5.
17. copolymer compositions according to claim 10, wherein X Shi – O-.
18. copolymer compositions according to claim 10, wherein X is-NR 5-.
19. copolymer compositions according to claim 10, wherein R 3there are at least 3 and the straight or branched alkyl of 12 carbon atoms at the most.
20. copolymer compositions according to claim 19, wherein R 3propyl group, butyl and hexyl.
The method of 21. production polymkeric substance, described method comprises the polymerization of the monomer composition with following structure:
Wherein R 1be selected from hydrogen atom or the alkyl containing at least one carbon atom; R 2be selected from the alkyl containing at least one carbon atom; X represents-NR 5-group, and Y Biao Shi – NR 3r 4-group, wherein R 3, R 4, and R 5represent hydrogen atom or the alkyl containing at least one carbon atom independently, in addition, R 3and R 4in one can represent lone-pair electron; Subscript n represents it is the integer of 1-12; And subscript m represents it is the integer of 1-12; Wherein said alkyl independently and optionally by least one heteroatoms or heteroatom group replace.
22. methods according to claim 21, wherein said polymerization is free radical polymerization.
23. methods according to claim 22, wherein said free radical polymerization is RAFT polymerization, wherein in described RAFT polymerization, monomer composition according to claim 1 issues raw radical polymerization in the condition that there is at least one thio-carbonyl sulfide chain-transfer agent and radical initiator.
24. methods according to claim 22, wherein said free radical polymerization is ATRP polymerization, wherein in described ATRP polymerization, monomer composition according to claim 1 issues raw radical polymerization in the condition that there is ATRP catalyzer and ATRP inhibitor.
The method of 25. production multipolymers, described method comprises:
I () will have the monomer composition polymerization of following chemical structure,
Wherein R 1be selected from hydrogen atom or the alkyl containing at least one carbon atom; R 2for hydrogen atom; X represents-NR 5-group, wherein R 5represent hydrogen atom or the alkyl containing at least one carbon atom, and Y represents-O-group; Subscript n represents it is the integer of 1-12; And subscript m represents it is the integer of 1-12; Wherein said alkyl independently and optionally by least one heteroatoms or heteroatom group replace;
To produce the precursor polymer with carboxylic acid terminal groups; And
(ii) functional groups being selected from amino group, mercapto groups and alkoxide groups is used to replace the OH radical moiety of described carboxylic acid terminal groups.
The method of 26. production amide group copolymer derivatives, described method comprises:
I () will have the monomer composition polymerization of following chemical structure,
Wherein R 1be selected from hydrogen atom or the alkyl containing at least one carbon atom; R 2for the hydrocarbon containing at least one carbon atom
Base; X represents-NR 5-group, wherein R 5represent hydrogen atom or the alkyl containing at least one carbon atom, and Y represents-O-group; Subscript n represents it is the integer of 1-12; And subscript m represents it is the integer of 1-12; Wherein said alkyl independently and optionally by least one heteroatoms or heteroatom group replace;
To produce precursor polymer; And
(ii) by amide group, functionalization is carried out to produce amido polymer derivative to described precursor polymer, the O-R of wherein said precursor polymer 2group at least partially replace by amino group, thus obtain amido polymer derivant, wherein said monomeric unit there is chemical structure according to claim 10 at least partially.
27. methods according to claim 26, wherein by using the amide condensed dose of functionalization realizing amide group.
28. methods according to claim 27, wherein said amide condensed dose is 4-(4,6-dimethoxy-1,3,5-triazines base-2-base)-4-methylmorpholinium chloride (DMTMM).
The combinatorial library of 29. copolymer compositions according to claim 10, the one or more of wherein said copolymer compositions are selected from X, Y, R 1, R 2, n, m and p variable change.
The composition libraries of 30. pairs of copolymer compositions according to claim 10 carries out high flux screening to resolve the method for its LCST character, and described method comprises carries out high-throughput spectral luminosity Measurement and analysis to determine described LCST character to the combinatorial library of described copolymer compositions.
CN201180033546.1A 2010-05-06 2011-05-06 Adjustable LCST polymkeric substance and preparation method thereof Expired - Fee Related CN102971348B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201510556416.6A CN105175623A (en) 2010-05-06 2011-05-06 Tunable LCST polymers and methods of preparation

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US33198710P 2010-05-06 2010-05-06
US61/331,987 2010-05-06
PCT/US2011/035453 WO2011140409A2 (en) 2010-05-06 2011-05-06 Tunable lcst polymers and methods of preparation

Related Child Applications (1)

Application Number Title Priority Date Filing Date
CN201510556416.6A Division CN105175623A (en) 2010-05-06 2011-05-06 Tunable LCST polymers and methods of preparation

Publications (2)

Publication Number Publication Date
CN102971348A CN102971348A (en) 2013-03-13
CN102971348B true CN102971348B (en) 2015-09-30

Family

ID=44904495

Family Applications (2)

Application Number Title Priority Date Filing Date
CN201510556416.6A Pending CN105175623A (en) 2010-05-06 2011-05-06 Tunable LCST polymers and methods of preparation
CN201180033546.1A Expired - Fee Related CN102971348B (en) 2010-05-06 2011-05-06 Adjustable LCST polymkeric substance and preparation method thereof

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CN201510556416.6A Pending CN105175623A (en) 2010-05-06 2011-05-06 Tunable LCST polymers and methods of preparation

Country Status (3)

Country Link
US (1) US20130123144A1 (en)
CN (2) CN105175623A (en)
WO (1) WO2011140409A2 (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9249250B2 (en) * 2014-01-15 2016-02-02 University Of South Carolina Butadiene-derived polymers grafted nanoparticles and their methods of manufacture and use
CN114773510A (en) * 2022-03-09 2022-07-22 广州大学 Biological-mediated RAFT polymerization method

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7279176B1 (en) * 1999-09-02 2007-10-09 Rice University Nitric oxide-producing hydrogel materials

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0597699A (en) * 1991-10-04 1993-04-20 Fuji Photo Film Co Ltd Cancer metastasis inhibitor composed of propenamide derivative polymer
US6294390B1 (en) * 1996-07-22 2001-09-25 Novartis Ag Covalently immobilized fluoroionophores for optical ion sensors
US20050276858A1 (en) * 2001-04-23 2005-12-15 Kao Weiyuan J Bifunctional-modified hydrogels
FR2824832B1 (en) * 2001-05-16 2005-05-27 Oreal WATER-SOLUBLE WATER-SOLUBLE SKELETOLYMERIC POLYMERS WITH LCST LATERAL UNITS, PROCESS FOR THEIR PREPARATION, AQUEOUS COMPOSITIONS CONTAINING SAME, AND USE THEREOF IN THE COSMETIC FIELD
US20050214250A1 (en) * 2003-11-06 2005-09-29 Harris J M Method of preparing carboxylic acid functionalized polymers
US20070095666A1 (en) * 2005-10-27 2007-05-03 Applera Corporation Surface Modification in a Manipulation Chamber
JP2009249512A (en) * 2008-04-07 2009-10-29 Canon Inc Structure and magnetic biosensor

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7279176B1 (en) * 1999-09-02 2007-10-09 Rice University Nitric oxide-producing hydrogel materials

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Bioactive modification of poly(ethylene glycol) hydrogels for tissue engineering;Junmin Zhu;《Biomaterials》;20100319;第31卷;第4639-4656页 *

Also Published As

Publication number Publication date
CN105175623A (en) 2015-12-23
US20130123144A1 (en) 2013-05-16
WO2011140409A3 (en) 2012-03-15
WO2011140409A2 (en) 2011-11-10
CN102971348A (en) 2013-03-13

Similar Documents

Publication Publication Date Title
US9644119B2 (en) Material self-assembly method and selective adhesion method based on molecular recognition
US8840339B2 (en) Soil remediation process
Pasetto et al. Synthesis and characterisation of molecularly imprinted catalytic microgels for carbonate hydrolysis
CN104302783B (en) Conjugated polymer beads and preparation method thereof
KR20140012941A (en) Continuous flow polymerisation process
Maji et al. A stimuli-responsive methionine-based zwitterionic methacryloyl sulfonium sulfonate monomer and the corresponding antifouling polymer with tunable thermosensitivity
Yu et al. New thermal-responsive polymers based on alanine and (meth) acryl amides
Günther et al. Polyelectrolytes with tunable charge based on polydehydroalanine: synthesis and solution properties
CN102971348B (en) Adjustable LCST polymkeric substance and preparation method thereof
Bodnarchuk et al. Polyelectrolyte p K a from experiment and molecular dynamics simulation
CN106496568A (en) Amphipathic copolymer networks of one kind cleaning anti-soil type and preparation method thereof
Wang et al. Preparation of a novel light-sensitive copolymer and its application in recycling aqueous two-phase systems
KR20220115564A (en) Novel sulfobetaine monomers, methods for their preparation, and uses thereof
Miao et al. Preparation of a novel thermo-sensitive copolymer forming recyclable aqueous two-phase systems and its application in bioconversion of Penicillin G
CN104861098B (en) Star polymer with pH stimulating responsiveness, preparation method thereof and application
Zhang et al. A general strategy for radical ring-opening polymerization of macrocyclic allylic sulfides
Xiao et al. Dual stimuli‐responsive polypeptide prepared by thiol‐ene click reaction of poly (l‐cysteine) and N, N‐dimethylaminoethyl acrylate
US20040266953A1 (en) Removal of the thiocarbonylthio or thiophosphorylthio end group of polymers and further functionalization thereof
US20200190237A1 (en) Branched polymers
JP5818245B2 (en) Isopropyl acrylamide derivative having azide group or alkyne group and polymer thereof
Hou et al. Synthesis of two thermo-sensitive copolymers forming aqueous two-phase systems
AU2005335179B2 (en) Polyacrylamide gel for electrophoresis, polyacrylamide gel electrophoresis method using the same, method of producing the same and acrylamide compound
Chen et al. Synthesis and application of two light-sensitive copolymers forming recyclable aqueous two-phase systems
EP3492576A1 (en) Polymer gel for medium, medium, and method and kit for culturing cells
Wang et al. Poly (N-isopropylacrylamide) hydrogels fabricated via click chemistry: Well-defined α, ω-bis propargyl linear poly (N-isopropylacrylamide) s as crosslinkers

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20150930

Termination date: 20170506

CF01 Termination of patent right due to non-payment of annual fee